State newborn screening programs save thousands of lives as well as prevent serious morbidity, such as mental retardation, through the early detection and treatment of genetic conditions. Many more lives could be saved by expanding newborn screening to include additional disorders. Currently, newborn screening is not offered for disorders of sterol and bile acid metabolism.
Genetic alterations in sterol pathways result in the untimely mortality and morbidity caused by Smith-Lemli-Opitz syndrome (SLOS), familial hyper-cholesterolaemia (FH), cerebrotendinous xanthomatosis (CTX) and congenital adrenal hyperplasia (CAH). SLOS, FH and CAH were identified as conditions to consider for universal newborn screening in a recent American College of Medical Genetics report. Although CAH was a member of the screening panel ultimately recommended, SLOS and FH lacked a requisite criterion for inclusion; the availability of a suitable sensitive and selective screening test validated in a large population.
SLOS is an inborn error of cholesterol synthesis associated with cholesterol deficiency and involves accumulation of the cholesterol precursor 7-dehydrocholesterol and a derivative 8-dehydrocholesterol, as a result of reduced 7-dehydrocholesterol reductase activity. The incidence of SLOS is reported to be 1:20,000-40,000, but the carrier frequency may be as high as 1 in 30. Screening newborns for SLOS, in addition to enabling early institution of therapy, would allow genetic counseling. The “gold-standard” for confirmation of a SLOS diagnosis is gas chromatography (GC)-MS determination of the 7- and 8-dehydrocholesterol levels and their ratio to cholesterol in plasma.
FH is the most common serious genetic condition in the US, with a reported incidence as high as 1:500. FH has no phenotype at birth other than elevated plasma low density lipoprotein (LDL)-cholesterol due to various heterozygous defects in the LDL receptor gene or intracellular processing of the LDL-receptor complex. Although detection of elevated plasma LDL-cholesterol has been used in many studies as a surrogate for FH diagnosis, the “gold-standards” include either molecular genetic studies identifying a pathogenic mutation in the LDL-cholesterol receptor gene or biochemical studies showing defective LDL-cholesterol receptor activity in cultured fibroblasts. In the US population, the large number of identified mutations, along with assay expense and lack of general availability of both assays, makes identification via LDL-cholesterol mutation analysis or receptor activity impractical.
CTX is a rare genetic sterol condition caused by mutations in the CYP27A gene. The associated P450 enzyme is important in production of bile acids and when sterol 27-hydroxylase activity is blocked, substrates such as 7α-hydroxy-4-cholestene-3-one accumulate. CTX characteristically presents in childhood or adult life with symptoms caused by the accumulation in various tissues of cholesterol and cholestanol, formed in part from the elevated 7α-hydroxy-4-cholestene-3-one. Common CYP27A gene mutations have been identified with increased prevalence in several world populations and DNA screening has been suggested as a tool to enable diagnosis and genetic counseling in those countries.
CAH is the most common inborn error of the adrenal steroid pathways and is caused by mutations in the CYP21A2 gene in >90% of cases. The resulting steroid hormone imbalance, involving accumulation of the 21-hydroxylase substrate 17α-hydroxyprogesterone (17OHP), leads to salt-wasting crises in the newborn period. Pre-symptomatic diagnosis and hormone replacement therapy can be life-saving and screening for CAH by immunoassay measurement of 17OHP has been integrated into many newborn screening programs. One reason CAH screening has not been universal is the number of false positives associated with immunoassay 17OHP measurement.
Due to the impact of these conditions, there is still a need for a suitable sensitive and selective screening test for SLOS, FH, and CTX for early identification of the conditions. Such a screening test may also be applicable to other conditions, such as CAH. Similarly, screening may be used for various bile acid disorders exhibited in part by altered sterols in the body.